The studies of the fragment complexes of staphylococcal nuclease, RNase A and cytochrome c have led us to the hypothesis that after folding of almost the entire polypeptide chain (including the S-S bonds in the case of RNase A) the interatomic interactions would be globally coupled to generate extra force for shifting the equilibrium of folding and unfolding in favor of folding. To understand this extra force and speculating that some of evolutionarily invariant amino acids might play a role we have investigated the effect of substitution of invariant proline 30, leucine 32 and glycine 34 and partially invariant Leu 35 of cytochrome c using the three-fragment complex of horse cytochrome c as described in the previous years. The first phase of this work is now complete with important results: (1) The extra force would not be van der Waals interaction, hydrogen bond, hydrophobic interaction or electrostatic interaction per se, i.e. this force would be a new type of interaction having a property of delocalization; (2) The extra force would constrain the atomic positions of individual residues in a concerted manner throughout the structure; (3) The extra force would be detectable on the basis of perturbation of enthalpy and entropy changes (the same sign) associated with folding by substitution of some specific amino acid such as evolutionarily invariant one after taking into account the contributions of possible perturbation of the unfolded form. In the case of cytochrome c the extra force would be stronger for the reduced form than for the oxidized form thus modulating the redox potential. Further, the studies of hybrid complexes using fragments from horse, tuna, Candida krusei, and yeast cytochromes c have indicated that the information for the cytochrome c fold is exchangeable between the fragments of phylogenetically distant species as measured by ligation of Met 80 to the heme iron, and suggested that; (a) however, mutation of a few specific amino acids or perhaps a single amino acid could alter stabilization of the Met 80-S-heme-Fe bond; (b) such destabilization could be reversed by mutation at some other position or positions.